Vaccine failure in HIV infection mediated by Myeloid derived suppressor cells (MDSCs) The overall goal of this proposal is to elucidate the mechanisms by which HIV infection induces myeloid derived suppressor cells (MDSCs) and their role in HBV vaccine failure in HIV-infected individuals, with an aim to develop effective approaches to improve vaccine efficacy in the immunocompromised host. To this end, we will use a model of HBV vaccine response in HIV infection, since co-infection of HBV and HIV is common due to shared risk factors, and as such HBV vaccine is required to prevent co-infection and its associated morbidity and mortality. HBV vaccine responses in HIV-infected individuals are, however, often blunted, with only 30-60% seroconversion (anti-HBs > 10 IU/ml) compared to a 90-95% success rate in healthy subjects (HS). This poor vaccine response is also observed for influenza and pneumococcal vaccinations in HIV+ subjects and other immunocompromised hosts, including the elderly. Attempts to improve the efficacy of immunizations in both infected and aged humans have been unsuccessful, in part due to our poor understanding of the mechanisms that dampen vaccine responses in these settings. Importantly, we and others have recently found that chronic viral (HIV, HCV) infection is often associated with an expansion of MDSCs - a heterogeneous population of immature and potently immunosuppressive myeloid cells that are generated due to aberrant myelopoiesis, often observed during various infections and cancers. Recently, we have demonstrated that suppressive MDSCs expand, promote regulatory T (Treg) cell development, and inhibit effector T (Teff) cell functions in HIV+ subjects, even in those on antiretroviral therapy (ART) with undetectable viremia. We discovered that expressions of microRNA (miR)-124 and its target, the signal transducer and activator of transcription 3 (STAT-3), are dysregulated in MDSCs from HIV+ subjects. To date, how MDSCs are induced in the setting of HIV infection and their roles in HBV vaccine failure, however, remain largely unknown. In this proposal, we hypothesize that miR-124-mediated STAT-3 signaling plays a pivotal role in induction of MDSCs, which can suppress HBV vaccine responses in HIV-infected individuals. To test this hypothesis, we designed the following two specific aims: Aim 1 will elucidate the mechanisms of MDSC induction via miR-124-mediated activation of STAT3 pathway; Aim 2 will characterize the role of MDSCs in HBV vaccine responses in HIV-infected individuals. This translational study is important in that it will provide a working model to explore mechanisms that may be fundamental to diminishing the immune (vaccine) responses observed in HIV infection and other chronic infectious diseases. Understanding such mechanisms are critical for developing approaches to improve vaccine efficacy in HIV-infected individuals, with relevance that may extend to other immunocompromised conditions such as HCV infection, hemodialysis, immunosuppression, transplantation, and malignancy in general. This project will in addition expose our undergraduate and graduate students to state-of- the-art a state-of-the-art research program.